nonaene ( SB 1578 ) , a Potent Inhibitor of Janus Kinase 2 / Fms-LikeTyrosine Kinase-3 ( JAK 2 / FLT 3 ) for the Treatment of Rheumatoid Arthritis

Herein, we describe the synthesis and SAR of a series of small molecule macrocycles that selectively inhibit JAK2 kinase within the JAK family and FLT3 kinase. Following a multiparameter optimization of a key aryl ring of the previously described SB1518 (pacritinib), the highly soluble 14l was selected as the optimal compound. Oral efficacy in the murine collageninduced arthritis (CIA) model for rheumatoid arthritis (RA) supported 14l as a potential treatment for autoimmune diseases and inflammatory disorders such as psoriasis and RA. Compound 14l (SB1578) was progressed into development and is currently undergoing phase 1 clinical trials in healthy volunteers. ■ INTRODUCTION An estimated 1% of the world’s population is afflicted by rheumatoid arthritis (RA), a chronic, systemic inflammatory disorder leading to the destruction of articular cartilage and ankylosis of the joints. RA is a disabling and painful condition, which leads to substantial loss of functioning and mobility if not adequately treated. Nonpharmacological treatment includes physical, occupational, and nutritional therapy, but these do not stop the progression of joint destruction. Analgesic and antiinflammatory drugs, including steroids, are used to suppress the symptoms, while disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, hydroxychloroquin, and sulfasalazine, modify the underlying immune process in an effort to prevent long-term damage. Although many patients derive benefit from DMARDs, few achieve remission, and there are many adverse events related to the liver, bone marrow, and renal toxicity, allergic skin reactions, autoimmunity and infections. More recently, the advent of biological agents targeted at proinflammatory cytokines, such as the anti-TNFα drugs etanercept, infliximab, and adalimumab, have successfully suppressed inflammation in many individuals with rheumatoid arthritis (RA). However, these and other biologics are expensive drugs with significant side effects, and the majority of patients relapse when treatment is withdrawn. Inhibition of protein kinases implicated in cytokine signaling networks has emerged as a potential new treatment paradigm for RA. The hematopoietin family of cytokines, which includes several postulated to have roles in RA (e.g., interferons, IL-2, IL-6, IL-7, IL-12, and IL-15), bind to Type I and II cytokine receptors and signal through the janus kinase-signal transducer and activator of the transcription (JAK-STAT) pathway. There are 4 members of the JAK kinase family (JAK1, JAK2, JAK3, and TYK2 (tyrosine kinase 2)) which play essential roles in several important physiological processes such as hematopoiesis and lipid homeostasis. JAK inhibitors with a range of selectivity profiles have been described with many now in clinical trials for treatment of various cancers (JAK1/2) and for immunosuppressive disorders (JAK3). However, the immunosuppressive effects of inhibiting JAK3 may cause severe combined immunodeficiency syndrome (SCID); hence, targeting selected JAK proteins is thought to be desirable. JAK2 plays an essential role in the signaling of pro-inflammatory cytokines involved in the pathogenesis of RA. Hence, JAK2 specific inhibitors may be differentiated from other JAK inhibitors and produce therapeutic benefits in inflammatory autoimmune diseases without immunosuppression. TYK2 is involved in Type I IFN signaling, Received: October 27, 2011 Published: February 17, 2012 Article